CYLD (cylindromatosis (turban tumor syndrome))

2010-05-01 Gilles Courtois Affiliation

INSERM U781, Hopital Necker-Enfants Malades, Paris, France

Identity

HGNC

CYLD

LOCATION

16q12.1

LOCUSID

1540

ALIAS

BRSS,CDMT,CYLD1,CYLDI,EAC,FTDALS8,MFT,MFT1,SBS,TEM,USPL2

FUSION GENES

Show Gene Fusions

DNA/RNA

Figure 1. CYLD gene. Coding exons are indicated in dark red. Asterisks indicate exons which are differentially spliced. One of the exon which is alternatively present (Reiley et al., 2004) encodes the binding site for TRAF2 and NEMO (Hövelmeyer et al., 2007).

Description

21 exons (17 coding) with alternative splicing (see figure 1). Size of the exons: 74 (bp), 98, 79, 136, 626, 302, 105, 8, 98, 116, 379, 165, 141, 122, 91, 66, 132, 108, 118, 216, 5611. The whole gene extends over approximately 56 kb.

Pseudogene

No.

Proteins

Figure 2. Structural organisation of CYLD. Binding sites for TRAF2 and NEMO are indicated. CAP: CAP-Gly domain, P: phosphorylation site, C and H: subdomains of the catalytic domain containing the Cys and His active residues.

Description

956 aa, approximately 110 kD.
Member of the deubiquitinase family (USP (Ubiquitin Specific Protease)) (Reyes-Turcu et al., 2009) with preferential affinity for K63-linked polyubiquitin chains (Massoumi and Paus, 2007; Courtois, 2008).

Expression

Ubiquitous.

Localisation

Cytoplasm (might bind to microtubules through its CAP-Gly domains).

Function

CYLD has been primarily identified as a negative regulator of NF-kappaB signaling, able to bind NEMO and TRAF2 and to deubiquitinate them (Brummelkamp et al., 2003; Kovalenko et al., 2003; Trompouki et al., 2003). It is also a negative regulator of JNK and p38 signaling pathways (Reiley et al., 2004) and IRF-3 signaling pathways (Friedman et al., 2008; Zhang et al., 2008). It participates in antimicrobial defense and inflammation by targeting ubiquitinated TRAF6 (Lim et al., 2007; Lim et al., 2008) and is required for the development and activation of immune cells (Reiley et al., 2006; Jin et al., 2007). CYLD may also affect cell proliferation/cell cycling by targeting Plk1 and HDAC6 (Stegmeier et al., 2007; Massoumi et al., 2009) and cell migration via microtubule assembly (Gao et al., 2008). It controls spermatogenesis by deubiquitinating RIP (Wright et al., 2007) and osteoclastogenesis by deubiquitinating TAK1 (Jin et al., 2008). A role for CYLD in the hypoxia response has been reported (An et al., 2008). Its inactivation by human papilloma virus-derived E6 protein results in hypoxia-induced NF-kappaB activation. Finally, it has been shown to affect calcium channel function by deubiquitinating TRPA1 (Stokes et al., 2006).
CYLD interacts with NEMO (Kovalenko et al., 2003; Trompouki et al., 2003), TRAF2 (Kovalenko et al., 2003; Trompouki et al., 2003), p62 (Wooten et al., 2008), Bcl-3 (Massoumi et al., 2006), TAK1 (Reiley et al., 2007), RIP (Wright et al., 2007), lck (Reiley et al., 2006), HDAC6 (Wickström et al., 2010).

Homology

Catalytic box (with other members of the deubiquitinase family (USPs)) and CAP-Gly (with a small collection of proteins (Steinmetz and Akhmanova, 2008)).

Mutations

Figure 3. Mutations of CYLD. Misense mutations are indicated by boxes, nonsense mutations by black brackets and frameshift mutations by orange bars. Compiled from Blake and Toro, 2009 with additions from Amaro et al., 2009; Kazakov et al., 2009; Nasti et al., 2009; Wang et al., 2010 and Kazakov et al., 2010.

Germinal

Tumor suppressor (Bignell et al., 2000).
See full recent listing in Blake and Toro, 2009. Most of the mutations (non sense, frameshit, splicing) would produce large deletions of the protein but, most likely, produce mRNA nonsense-mediated decay. Short truncations affect the catalytic box which extends to the carboxy-terminus of the protein and produce an inactive enzyme. Very few missense mutations have been reported. All of them affect the catalytic box.

Somatic

Loss of heterozygosity in developing tumors.

Implicated in

Entity name

Familial cylindromatosis and multiple trichoepithelioma

Note

Familial cylindromatosis, also called turban tumor syndrome is a rare inherited cancer which is characterized by the formation of benign tumors, called cylindroma, in hairy parts of the body, mostly the scalp. Cylindroma are considered as originating from a transformation event specifically affecting the folliculo-sebaceous-apocrine unit that produces hair and its associated glands. Early observations established that affected patients are heterozygous at birth for the locus causing the disease, whereas the cylindroma they develop exhibit a loss of heterozygosity (LOH) demonstrating the involvment of a gene coding for a tumor suppressor. More recently, it has been shown that another genetic disease sharing similarities with familial cylindromatosis, multiple trichoepithelioma (MT), is also caused by CYLD mutations (For reviews, see Massoumi and Paus, 2007; Courtois, 2008; Amaro et al., 2009).

Entity name

Various cancers

Note

Loss of CYLD has been reported in solid tumors of the colon and liver (Hellerbrand et al., 2007), kidney (Ströbel et al., 2002), cervix (Hirai et al., 2004) and prostate (Kikuno et al., 2008). CYLD is also epigenetically silenced in some non-small-cell lung cancers (NSCLC) (Zhong et al., 2007).
In the case of melanoma, it has been shown that the CYLD promoter region is under negative control by snail, a protein which is upregulated in this disease (Massoumi et al., 2009). CYLD down-regulation results in Bcl3/NF-kappaB activation.

Article Bibliography

Pubmed ID	Last Year	Title	Authors
19929939	2010	Multiple trichoepitheliomas--a novel mutation in the CYLD gene.	Amaro C et al
18977328	2008	Inactivation of the CYLD deubiquitinase by HPV E6 mediates hypoxia-induced NF-kappaB activation.	An J et al
17692804	2007	Frequent engagement of the classical and alternative NF-kappaB pathways by diverse genetic abnormalities in multiple myeloma.	Annunziata CM et al
10835629	2000	Identification of the familial cylindromatosis tumour-suppressor gene.	Bignell GR et al
19462465	2009	Update of cylindromatosis gene (CYLD) mutations in Brooke-Spiegler syndrome: novel insights into the role of deubiquitination in cell signaling.	Blake PW et al
12917690	2003	Loss of the cylindromatosis tumour suppressor inhibits apoptosis by activating NF-kappaB.	Brummelkamp TR et al
18193168	2008	Tumor suppressor CYLD: negative regulation of NF-kappaB signaling and more.	Courtois G et al
18636086	2008	The tumour suppressor CYLD is a negative regulator of RIG-I-mediated antiviral response.	Friedman CS et al
18222923	2008	The tumor suppressor CYLD regulates microtubule dynamics and plays a role in cell migration.	Gao J et al
16774947	2007	Reduced expression of CYLD in human colon and hepatocellular carcinomas.	Hellerbrand C et al
15010838	2004	Conventional and array-based comparative genomic hybridization analyses of novel cell lines harboring HPV18 from glassy cell carcinoma of the uterine cervix.	Hirai Y et al
17923499	2007	Regulation of B cell homeostasis and activation by the tumor suppressor gene CYLD.	Hövelmeyer N et al
17609426	2007	Gene mapping and expression analysis of 16q loss of heterozygosity identifies WWOX and CYLD as being important in determining clinical outcome in multiple myeloma.	Jenner MW et al
18382763	2008	Deubiquitinating enzyme CYLD negatively regulates RANK signaling and osteoclastogenesis in mice.	Jin W et al
17392286	2007	Deubiquitinating enzyme CYLD regulates the peripheral development and naive phenotype maintenance of B cells.	Jin W et al
20132422	2010	Brooke-Spiegler syndrome: report of a case with a novel mutation in the CYLD gene and different types of somatic mutations in benign and malignant tumors.	Kazakov DV et al
17692805	2007	Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma.	Keats JJ et al
18431742	2008	Genistein mediated histone acetylation and demethylation activates tumor suppressor genes in prostate cancer cells.	Kikuno N et al
12917691	2003	The tumour suppressor CYLD negatively regulates NF-kappaB signalling by deubiquitination.	Kovalenko A et al
18643924	2008	CYLD is a crucial negative regulator of innate immune response in Escherichia coli pneumonia.	Lim JH et al
17925880	2007	Tumor suppressor CYLD acts as a negative regulator for non-typeable Haemophilus influenza-induced inflammation in the middle ear and lung of mice.	Lim JH et al
19124656	2009	Down-regulation of CYLD expression by Snail promotes tumor progression in malignant melanoma.	Massoumi R et al
19807742	2009	Five novel germline function-impairing mutations of CYLD in Italian patients with multiple cylindromas.	Nasti S et al
15496400	2004	Negative regulation of JNK signaling by the tumor suppressor CYLD.	Reiley W et al
17548520	2007	Deubiquitinating enzyme CYLD negatively regulates the ubiquitin-dependent kinase Tak1 and prevents abnormal T cell responses.	Reiley WW et al
16501569	2006	Regulation of T cell development by the deubiquitinating enzyme CYLD.	Reiley WW et al
19489724	2009	Regulation and cellular roles of ubiquitin-specific deubiquitinating enzymes.	Reyes-Turcu FE et al
17495026	2007	The tumor suppressor CYLD regulates entry into mitosis.	Stegmeier F et al
18835717	2008	Capturing protein tails by CAP-Gly domains.	Steinmetz MO et al
16500080	2006	TRPA1 is a substrate for de-ubiquitination by the tumor suppressor CYLD.	Stokes A et al
11756779	2002	Spiradenocylindroma of the kidney: clinical and genetic findings suggesting a role of somatic mutation of the CYLD1 gene in the oncogenesis of an unusual renal neoplasm.	Ströbel P et al
12917689	2003	CYLD is a deubiquitinating enzyme that negatively regulates NF-kappaB activation by TNFR family members.	Trompouki E et al
19911186	2010	A novel missense mutation of CYLD gene in a Chinese family with multiple familial trichoepithelioma.	Wang FX et al
19893491	2010	CYLD negatively regulates cell-cycle progression by inactivating HDAC6 and increasing the levels of acetylated tubulin.	Wickström SA et al
18174161	2008	Essential role of sequestosome 1/p62 in regulating accumulation of Lys63-ubiquitinated proteins.	Wooten MW et al
17981138	2007	Regulation of early wave of germ cell apoptosis and spermatogenesis by deubiquitinating enzyme CYLD.	Wright A et al
18467330	2008	Regulation of IkappaB kinase-related kinases and antiviral responses by tumor suppressor CYLD.	Zhang M et al
17043644	2007	Pharmacologic inhibition of epigenetic modifications, coupled with gene expression profiling, reveals novel targets of aberrant DNA methylation and histone deacetylation in lung cancer.	Zhong S et al

Other Information

Locus ID:

NCBI: 1540
MIM: 605018
HGNC: 2584
Ensembl: ENSG00000083799

Variants:

dbSNP: 1540
ClinVar: 1540
TCGA: ENSG00000083799
COSMIC: CYLD

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000083799	ENST00000311559	Q9NQC7
ENSG00000083799	ENST00000398568	Q9NQC7
ENSG00000083799	ENST00000398568	A0A024R6T1
ENSG00000083799	ENST00000427738	Q9NQC7
ENSG00000083799	ENST00000562884	J3QKR2
ENSG00000083799	ENST00000564326	Q9NQC7
ENSG00000083799	ENST00000564326	A0A024R6T1
ENSG00000083799	ENST00000564634	H3BPZ5
ENSG00000083799	ENST00000566024	I3L117
ENSG00000083799	ENST00000566206	J3KRR7
ENSG00000083799	ENST00000566679	H3BSW9
ENSG00000083799	ENST00000568704	H3BS09
ENSG00000083799	ENST00000569418	Q9NQC7
ENSG00000083799	ENST00000569418	A0A024R6T1
ENSG00000083799	ENST00000569681	H3BTB8

Expression (GTEx)

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
RIG-I-like receptor signaling pathway	KEGG	ko04622
RIG-I-like receptor signaling pathway	KEGG	hsa04622
Osteoclast differentiation	KEGG	ko04380
Osteoclast differentiation	KEGG	hsa04380
Metabolism of proteins	REACTOME	R-HSA-392499
Post-translational protein modification	REACTOME	R-HSA-597592
Immune System	REACTOME	R-HSA-168256
Innate Immune System	REACTOME	R-HSA-168249
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways	REACTOME	R-HSA-168643
NOD1/2 Signaling Pathway	REACTOME	R-HSA-168638
RIG-I/MDA5 mediated induction of IFN-alpha/beta pathways	REACTOME	R-HSA-168928
Negative regulators of RIG-I/MDA5 signaling	REACTOME	R-HSA-936440
Signal Transduction	REACTOME	R-HSA-162582
Death Receptor Signalling	REACTOME	R-HSA-73887
TNF signaling	REACTOME	R-HSA-75893
TNFR1-induced proapoptotic signaling	REACTOME	R-HSA-5357786
TNFR1-induced NFkappaB signaling pathway	REACTOME	R-HSA-5357956
Regulation of TNFR1 signaling	REACTOME	R-HSA-5357905
Deubiquitination	REACTOME	R-HSA-5688426
Ub-specific processing proteases	REACTOME	R-HSA-5689880

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
37162682	2024	YTHDC2 Retards Cell Proliferation and Triggers Apoptosis in Papillary Thyroid Cancer by Regulating CYLD-Mediated Inactivation of Akt Signaling.	2
38246916	2024	CYLD regulates cell ferroptosis through Hippo/YAP signaling in prostate cancer progression.	1
38287022	2024	CYLD induces high oxidative stress and DNA damage through class I HDACs to promote radiosensitivity in nasopharyngeal carcinoma.	0
38319288	2024	TNF and IFNγ-induced cell death requires IRF1 and ELAVL1 to promote CASP8 expression.	0
38579060	2024	Megalosplenia as an initial manifestation of multiple myeloma with a novel CYLD gene mutation: A case report and literature review.	0
37162682	2024	YTHDC2 Retards Cell Proliferation and Triggers Apoptosis in Papillary Thyroid Cancer by Regulating CYLD-Mediated Inactivation of Akt Signaling.	2
38246916	2024	CYLD regulates cell ferroptosis through Hippo/YAP signaling in prostate cancer progression.	1
38287022	2024	CYLD induces high oxidative stress and DNA damage through class I HDACs to promote radiosensitivity in nasopharyngeal carcinoma.	0
38319288	2024	TNF and IFNγ-induced cell death requires IRF1 and ELAVL1 to promote CASP8 expression.	0
38579060	2024	Megalosplenia as an initial manifestation of multiple myeloma with a novel CYLD gene mutation: A case report and literature review.	0
36922488	2023	MALT1-dependent cleavage of CYLD promotes NF-κB signaling and growth of aggressive B-cell receptor-dependent lymphomas.	4
37176077	2023	The Potential of Cylindromatosis (CYLD) as a Therapeutic Target in Oxidative Stress-Associated Pathologies: A Comprehensive Evaluation.	3
37549179	2023	CYLD stimulates macrophage phagocytosis of leukemic cells through STAT1 signalling in acute myeloid leukemia.	0
37725175	2023	Expanding CYLD protein in NF-κβ/TNF-α signaling pathway in response to Lactobacillus acidophilus in non-metastatic rectal cancer patients.	0
37865315	2023	An siRNA library screen identifies CYLD and USP34 as deubiquitinases that regulate GPCR-p38 MAPK signaling and distinct inflammatory responses.	0

Citation

Gilles Courtois

CYLD (cylindromatosis (turban tumor syndrome))

Atlas Genet Cytogenet Oncol Haematol. 2010-05-01

Online version: http://atlasgeneticsoncology.org/gene/40232/cyld-(cylindromatosis-(turban-tumor-syndrome))